Thymocyte glucocorticoid resistance alters positive selection and inhibits autoimmunity and lymphoproliferative disease in MRL-lpr/lpr mice.
Thymus-derived glucocorticoids antagonize T cell receptor (TCR)-induced thymocyte apoptosis, allowing the survival (positive selection) of cells bearing TCRs that recognize self antigens with low-to-moderate avidity. Here we demonstrate that expression of an antisense glucocorticoid receptor transgene in thymocytes of spontaneously autoimmune MRL-lpr/lpr mice causes the loss of specific TCR Vbeta-bearing T cells that are normally positively selected in this strain. These transgenic mice had lower autoantibody production and milder symptoms of autoimmune disease than MRL-lpr/lpr controls and had markedly reduced accumulation of the TCR+Thy-1+CD4-CD8-B220+ T cells that are the hallmark of the lpr mutation. Thus, decreased glucocorticoid signaling in thymocytes alters the T cell repertoire and greatly diminishes autoimmunity in MRL-lpr/lpr autoimmune mice.
Tolosa
E
E
Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1152, USA.
King
L B
LB
Ashwell
J D
JD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000502:physiology; D004247:DNA / Q000276:immunology; D016373:DNA, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013268:Stimulation, Chemical; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D019076:Transgenes
D001323:Autoantibodies; D016373:DNA, Antisense; D008934:Mitogens; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D004247:DNA